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Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer is the most diagnosed type of cancer amongst women in economically developing countries and globally. Most breast cancers express estrogen receptor alpha (ERα) and are categorized as positive (ER + ) breast cancer. Endocrine therapies such as, selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor downregulators (SERDs) are used to treat ER + breast cancer. However, despite their effectiveness, severe side-effects and resistance are associated with these endocrine therapies. Thus, it would be highly beneficial to develop breast cancer drugs that are as effective as current therapies, but less toxic with fewer side effects, and less likely to induce resistance. Extracts of Cyclopia species, an indigenous South African fynbos plant, have been shown to possess phenolic compounds that exhibit phytoestrogenic and chemopreventive activities against breast cancer development and progression. In the current study, three well characterized Cyclopia extracts, SM6Met, cup of tea (CoT) and P104, were examined for their abilities to modulate the levels of the estrogen receptor subtypes, estrogen receptor alpha and estrogen receptor beta (ERβ), which have been recognized as crucial to breast cancer prognosis and treatment. We showed that the Cyclopia subternata Vogel ( C. subternata Vogel) extracts, SM6Met and cup of tea, but not the C. genistoides extract, P104, reduced estrogen receptor alpha protein levels while elevating estrogen receptor beta protein levels, thereby reducing the ERα:ERβ ratio in a similar manner as standard of care breast cancer endocrine therapies such as fulvestrant (selective estrogen receptor downregulator) and 4-hydroxytamoxifen (elective estrogen receptor modulator). Estrogen receptor alpha expression enhances the proliferation of breast cancer cells while estrogen receptor beta inhibits the proliferative activities of estrogen receptor alpha. We also showed that in terms of the molecular mechanisms involved all the Cyclopia extracts regulated estrogen receptor alpha and estrogen receptor beta protein levels through both transcriptional and translational, and proteasomal degradation mechanisms. Therefore, from our findings, we proffer that the C. subternata Vogel extracts, SM6Met and cup of tea, but not the C. genistoides extract, P104, selectively modulate estrogen receptor subtypes levels in a manner that generally supports inhibition of breast cancer proliferation, thereby demonstrating attributes that could be explored as potential therapeutic agents for breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Olayoku, Verhoog and Louw.)

Synergistic drug combinations are not only popular in antibiotic, anti-microbial, immune disease (i.e., AIDS) and viral infection studies, but has also gained traction in the field of cancer research as a multi-targeted approach. It has the potential to lower the doses needed of standard of care (SOC) therapeutic agents, whilst maintaining an effective therapeutic level. Lower dosages could ameliorate the fundamental problems such as drug resistance and metastasis associated with current SOC therapies. In the current study, we show that the combination of SM6Met with (2)-4-hydroxytamoxifen (4-OH-Tam, the active metabolite of tamoxifen) produces a strong synergistic effect in terms of inhibiting MCF7 ER-positive (ER + ) breast cancer cell proliferation and that a 20 times lower dose of 4-OH-Tam in combination with SM6Met is required to produce the same inhibitory effect on cell proliferation as 4-OH-Tam on its own. Cell cycle analyses of the best combination ratios of SM6Met and 4-OH-Tam also suggests that the combination results in increased accumulation of cells in the S-phase and in the apoptotic phase. Moreover, the best combination ratio (20:1) of SM6Met with 4-OH-Tam displayed greater anti-metastatic potential in terms of inhibiting ER + breast cancer cell migration, invasion, and colony formation than the SOC therapy alone, suggesting that SM6Met together with 4-OH-Tam could be a viable drug combination for not only delaying resistance and ameliorating the negative side-effects associated with current SOC therapies, like tamoxifen, but could also provide a novel, more affordable therapeutic alternative for treating or preventing ER + breast cancer metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Dyk, Verhoog and Louw.)

Acute phase proteins (APPs), such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP), are elevated in type-2 diabetes (T2D) and are routinely used as biomarkers for this disease. These APPs are regulated by the peripheral mediators of stress (i.e., endogenous glucocorticoids (GCs)) and inflammation (i.e., pro-inflammatory cytokines), with both implicated in the development of insulin resistance, the main risk factor for the development of T2D. In this review we propose that APPs, PAI-1, SAA, and CRP, could be the causative rather than only a correlative link between the physiological elements of risk (stress and inflammation) and the development of insulin resistance.

Central to the pharmacological use of glucocorticoids (GCs) is the availability of the glucocorticoid receptor alpha (GRα). However, chronic GC therapy often results in the ligand-mediated downregulation of the GRα, and the subsequent development of an acquired GC resistance. While studies have demonstrated the dimerization-dependent downregulation of GRα, as well as the molecular mechanisms through which ligand-mediated downregulation occurs, little is known regarding the relative contribution of these molecular mechanisms to the cumulative ligand-mediated downregulation of the receptor, especially within an endogenous system. Thus, to probe this, the current study evaluates the conformational-dependent regulation of GRα protein using mouse embryonic fibroblast (MEF) cells containing either wild type GRα (MEFwt) or the dimerization deficient GRα mutant (MEFdim) and inhibitors of transcription, translation, and proteasomal degradation. Results show that the promotion of GRα dimerization increases the downregulation of the receptor via two main mechanisms, proteasomal degradation of the receptor protein, and downregulation of GRwt mRNA transcripts. In contrast, when receptor dimerization is restricted these two mechanisms play a lesser role and results suggest that stabilization of GRα protein by non-coding RNAs may potentially be the major regulatory mechanism. Together, these findings clarify the relative contribution of the molecular mechanisms involved in ligand-mediated downregulation of GRα and provides pharmacological targets for the development of GRα ligands with a more favourable therapeutic index., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR dim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GR D/D ) have previously helped to define the functions of GR monomers and dimers. Since GR D/D retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GR D+L/D+L mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GR L/L mice (these mice have the I634A mutation but not the A465T mutation), displaying improper lung and skin formation. Using embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation assays, RNAseq, dimerization assays, and ligand-binding assays (and K d values), we found that the lethal phenotype in these mice is due to insufficient ligand binding. These data suggest there is some correlation between GR dimerization potential and ligand affinity. We conclude that even a mutation as subtle as I634A, at a position not directly involved in ligand interactions sensu stricto, can still influence ligand binding and have a lethal outcome., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the onset of severe side-effects, chronic GC therapy often leads to the ligand-mediated downregulation of the GRα which, in turn, leads to a decrease in GC sensitivity, and effectively, the development of acquired GC resistance. Although the ligand-mediated downregulation of GRα is well documented, the precise factors which influence this process are not well understood and, thus, the development of an acquired GC resistance presents an ever-increasing challenge to the pharmaceutical industry. Recently, however, studies have correlated the dimerization status of the GRα with its ligand-mediated downregulation. Therefore, the current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC-mediated GRα downregulation.

The development of resistance to glucocorticoids (GCs) in therapeutic regimens poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor α (GRα) underlie this resistance. Many studies have detailed how alterations in GRα function lead to diminished GC sensitivity; however, the current review highlights the wealth of data concerning reductions in the GRα pool, mediated by disease-associated and treatment-associated effects, which contribute to a significant decrease in GC sensitivity. Additionally, the current understanding of the molecular mechanisms involved in driving reductions in the GRα pool is discussed. After highlighting the importance of maintaining the level of the GRα pool to combat GC resistance, we present current strategies and argue that future strategies to prevent GC resistance should involve biased ligands with a predisposition for reduced GR dimerization, a strategy originally proposed as the SEMOGRAM-SEDIGRAM concept to reduce the side-effect profile of GCs.